tbuckley/cabot-search huggingface dataset:
HGG-29. How I treat recurrent pediatric high-grade glioma (HGG): A Europe-wide survey study.
Authors: Thomas Perwein, Barbara Giese, Gunther Nussbaumer, André O von Bueren, Miriam van Buiren, Martin Benesch, Christof Maria Kramm
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Prognosis of pediatric high-grade gliomas (pedHGG) is dismal, and there is no standard of care treatment in case of recurrence/progression. We aimed to gain an overview of different treatment strategies in the setting of recurrent/progressing pedHGG. METHODS: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on different therapeutic options in four real-world case scenarios (children/adolescents with recurrent/progressing HGG). RESULTS: One hundred and thirty-nine clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further active (multimodal) oncological treatment in three out of four cases and chose palliative care with pure symptom control measures only in one case (gliomatosis cerebri and marked symptoms). Depending on the case, 8-92% of experts would initiate a re-resection (maximal safe resection in case of localized hemispheric pedHGG), combined with molecular diagnostics, and 55-77% recommended (re-)irradiation, preferably local radiotherapy &amp;gt;20 Gy (or craniospinal irradiation in one case with disseminated spinal HGG, 65%). Throughout all case scenarios, most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitors, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% advocated immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumor-treating fields (1-26%), and intraventricular chemotherapy (4-24%). CONCLUSIONS: In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a standard (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressive HGG.
Whole-genome sequencing as an alternative to analyze copy number abnormalities in AML, MDS and MM.
Authors: Xiaodong Lyu, Tao Li, Dandan Zhu, Yuexin Cheng, Xiangxiang He, Zhenling Li, Shiyong Li, Shuaipeng Geng, Chunxiao Yao, Jingshuai Li, Yangwei Li, Yinyin Chang, Zunmin Zhu, Mao Mao, Yongping Song
Journal: Journal of Clinical Oncology (2022)

e19023 Background: Genomic alternations especially copy number aberrations (CNAs) are particularly imperative for diagnostic classification and risk stratification in patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and multiple myeloma (MM). With the technological advances of next generation sequencing (NGS), the current CCA test and the molecular tests are likely to be challenged by whole-genome sequencing (WGS), which is a more unbiased method to detect all types of genomic aberrations. Methods: 178 patients who met the clinical manifestations of blood malignancies were included in the study, including 89 patients with AML, 48 with MDS and 41 with MM. Bone marrow was collected and mononuclear cells were separated to harvest genomic DNA which was sequenced without capture at approximately 1x coverage depth (shallow whole-genome sequencing, sWGS). Genome-wide CNAs greater than 5 Mbp was analyzed for each sample. European Leukemia Net (ELN), Revised International Prognostic Scoring System (IPSS-R) or Revised International Staging System (R-ISS)-defining CNAs were selected and used to assign patients to a genetic risk group through the same classification systems that are used for CCA. Results: In this study, CNA events were identified in 109 (73.6%) patients via sWGS. By calculating frequencies of recurrent gains and losses at chromosome arm level, some recurrent events were detected like gains of chr 8 (observed in 12 AML and 9 MDS patients), chr 1 (observed in 18 MM patients), losses of chr 7 (observed in 9 AML and 3 MDS patients) and chr 13 (observed in 16 MM patients), which were consistent with previously reported cytogenetic events. Besides, amplifications of odd-numbered chromosomes were detected in 15(36.6%) of patients with multiple myeloma, including chromosomes 3, 5, 7, 9, 11, 15, 19 and/or 21. And the trisomy of chr 5, 7 or 9 are mainly observed with a frequency of 66.7%. Among 145 patients with CCA results, a high concordance of 97.7% (98.5%, 97.6% and 97.1% in AML, MDS and MM respectively) was achieved in CNA profiles at individual patient level with cytogenetics and/or FISH. Noteworthily, CNA events were detected in 20 of 28 (71.4%) MM patients with negative karyotyping results. Moreover, sWGS improved the overall diagnostic yield by reassign 18 patients (9 with AML and 9 with MDS) to risk categories with poorer prognosis. Nearly identical CNA profiles from the paired plasma and bone marrow suggest that peripheral blood may serve as a substitute to spare bone marrow aspiration. Conclusions: In summary, a streamlined sWGS provides an accurate, convenient and cost-effective approach to describe genomic profiles of CNAs in patients with AML, MDS and MM. Clinical trial information: ChiCTR2100052276.
The effect of breast radiotherapy parameters (XRT), chemotherapy regimens (CT) and dual anti-HER2 monoclonal antibodies (MoAb) on the development of cardiac dysfunction (CD) among patients with HER2-positive breast cancer from Saudi Arabia.
Authors: Atlal M. Abusanad, Omar Iskanderani, Marwan R. Al-hajeili, Reem Ujaimi
Journal: Journal of Clinical Oncology (2022)

e12508 Background: Treatment with anti-HER2 therapy can cause CD. The effect of breast XRT, heart dose and V25 of the heart and CT regimen on developing CD is controversial. The impact of these variables in developing CD among patients with HER2-positive breast cancer (BC), receiving CT plus anti-HER2 MoAb was evaluated in routine clinical practice. Methods: Patients with HER2-positive BC between 2015-2019 were included, retrospectively. CD is defined as a drop in (EF%) of at least 10 % points from baseline and/or below 50% at any point of the time during follow-up. The association of CD and various variables was examined with a significance level of &lt; 0.05. Results: Data from 224 female patients were analyzed with a mean age at diagnosis of 51 +12, BMI 29.6 ± 6.4, BSA 1.74 ± 0.19, 53% with left BC, 63% had non-metastatic BC, 52% with comorbidities, 11% had prior IHD medication use in 48%; metformin in 15% and B-blockers in 5%, 9.4% smoker, 70% had a mastectomy, 18% lumpectomy and 12% no surgery, 58% received XRT. The cumulative incidence of CD was 33% during follow-up noting that the first and subsequent drops of EF at any point of time during the follow-up was counted as a new event even for the same patient. The univariate analysis of factors influencing the risk of CD is shown in Table. However, the initial significance of CT regimen and whether the patient received breast XRT or otherwise, did not translate into significance on multivariate analysis with a P-value = 0.198 &amp; 0.326, respectively. Conclusions: XRT mean heart dose and V25 of the heart, anthracycline-based CT did not influence the risk of CD among this cohort. Likewise, the dual anti-HER2 therapy with trastuzumab and pertuzumab and the number of trastuzumab cycles did not influence CD. It is reassuring to demonstrate the safety of these approaches in real-life clinical practice.[Table: see text]
Randomized phase 2 study evaluating efficacy and safety of inupadenant in combination with chemotherapy in adults with metastatic non–small cell lung cancer (mNSCLC) who progressed on immunotherapy.
Authors: Mary E.R. O'Brien, Parneet K. Cheema, Christian Grohé, Enric Carcereny Costa, Nicolas Girard, Alberto Chiappori, Sally Ross, Maura Rossetti, Frederic Dubois, Joanne J. Lager, Shouryadeep Srivastava, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2022)

TPS9158 Background: In cancer, the accumulation of adenosine in the tumor microenvironment (TME) mediates immune suppression mainly via the high affinity A2A receptor (A2AR), causing dysregulation of innate and adaptative immune cell subsets and dampening the antitumor immune response. This results in increased tumor cell survival and immune escape (Blay 1997; Merighi 2003; Muller-Haegele 2014). Therefore, inhibiting A2AR could reverse immunosuppression and re-establish immune surveillance in the tumor microenvironment. Inupadenant is an antagonist of the A2AR with potent inhibition of A2AR even at the high concentrations of adenosine present in the tumor microenvironment. Ongoing clinical studies have established inupadenant as a molecule with a favorable safety profile with preliminary evidence of clinical activity in multiple tumor types, including durable PRs in patients who have exhausted standard treatment options (Buisseret 2021). The standard treatment for patients without a driving mutation who progress on first-line IO is a platinum-based doublet chemotherapy regimen. Carboplatin plus Pemetrexed (C+P) is the preferred chemotherapy in nonsquamous mNSCLC. Study A2A-005 will evaluate the efficacy of inupadenant in combination with C+P as a second-line therapy in adult patients with nonsquamous mNSCLC (post-IO). A successful outcome from study A2A-005 will help address a high unmet need for this patient population and could lead to new therapeutic options. Methods: This is a 2-part study. The first part is an open label dose-finding part to determine the safety and recommended Phase 2 dose (RP2D) of inupadenant in combination with C+P (N = 40). In Part 2, 150 patients will be randomized 1:1 to inupadenant or placebo, both in combination with C+P. Tumor response will be determined according to RECIST 1.1 criteria and safety findings will be reviewed by the Safety Review Committee (for Part 1) and the Data Monitoring Committee (for Part 2). Key eligibility criteria include 1) mNSCLC of nonsquamous pathology, 2) have received only 1 line of anti-PD-(L)1 therapy in the metastatic setting, without concomitant chemotherapy, and have progressed (IO/IO combination therapy is allowed), 3) have measurable disease as defined by RECIST v1.1 criteria and 4) Eastern Cooperative Oncology Group status ≤1. Primary endpoints are RP2D (for Part 1) and PFS (for Part 2). Secondary endpoints include change in tumor size, ORR, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. The study will be conducted in approximately 11 countries in North America and Europe. Clinical trial information: EudraCT 2021-005487-22.
RARE-21<i>Sox2</i> plays an important role in choroid plexus tumor development
Authors: Lukas Faltings, Tamanna Sarowar, James Virga, Navleen Singh, Brightlyn Kwa, Haotian Zhao
Journal: Neuro-Oncology (2022)

Abstract Choroid plexus (CP) tumors are rare primary brain neoplasms found most commonly in children and are thought to arise from CP epithelial cells. Sox2 is a transcription factor that not only plays a role in development in the ventricular zone, CP, and roof plate, but also contributes to cancer stemness, tumorigenesis, and drug resistance. Gene expression studies demonstrate aberrant Sox2 expression in human CP tumors, suggesting a role in tumor development. A subset of CP tumors exhibit abnormal NOTCH pathway activity. Using animal models, we previously show that sustained NOTCH activity leads to CP tumors. Immunofluorescence, RT-qPCR, and RNA scope assays have revealed increased Sox2 levels in NOTCH-driven CP tumors compared to wild type CP in mice. To investigate the role of Sox2 in CP tumors, we eliminated Sox2 expression in NOTCH-driven CP tumors. Loss of Sox2 almost completely blocked NOTCH-driven CP tumor growth in these mice, supporting a role for Sox2 in these tumors. Ciliation regulation is one proposed functional pathway for tumorigenesis in CP tumors. Using immunofluorescence assays for cilia (ARL13b) and aquaporin transport protein 1 (AQP1) in combination with super resolution microscopy, we observe a stark contrast between wild type CP epithelial cells which are multiciliated and homogeneously express AQP1, indicative of normal epithelial differentiation, compared to NOTCH-driven CP tumors consisting of mono-ciliated cells with loss of AQP1 expression. In Sox2-deficient NOTCH-driven CP tumors, we observe tumor cells remain mono-ciliated and AQP1-negative, indicating that Sox2 loss does not affect the ciliation machinery. Together this warrants further study into the mechanisms of Sox2 functions in CP tumors. By unraveling the role of Sox2 in CP tumors, we may better understand their origin and biology to ultimately design improved treatment options.
HGG-06. Phase 2 Study of Veliparib and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients with Newly Diagnosed High-Grade Glioma without H3 K27M or BRAF Mutations: A Report from the Children's Oncology Group ACNS1721 Study
Authors: Matthias Karajannis, Arzu Onar-Thomas, Patricia Baxter, Nina Butingan, Christine Fuller, Amar Gajjar, Sofia Haque, Nada Jabado, Tong Lin, John Lucas, Shannon MacDonald, Celeste Matsushima, Namrata Patel, Christopher Pierson, Linda Springer, Eileen Stark, Mark Souweidane, Michael Walsh, Wafik Zaky, Maryam Fouladi, Kenneth Cohen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Preclinical data indicates that veliparib crosses the blood-brain-barrier and enhances the efficacy of radiotherapy and temozolomide in IDH mutant and wild-type HGG models. ACNS1721 was a single-arm, non-randomized phase 2 clinical trial designed to determine whether treatment with veliparib and radiotherapy, followed by the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and temozolomide, improves progression-free survival (PFS) in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. METHODS: Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients without somatic H3 K27M or BRAF mutations were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Protocol radiochemotherapy consisted of involved field radiotherapy with concurrent veliparib at 65 mg/m2 twice daily. Adjuvant chemotherapy consisted of up to 10 cycles of veliparib 25 mg/m2 twice daily and temozolomide 135 mg/m2 once daily for 5 days every 4 weeks. RESULTS: Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year progression-free survival (PFS) was 0.29 (SE = 0.09) and 1-year overall survival (OS) was 0.67 (SE = 0.10). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year PFS was 0.57 (SE = 0.15) and 1-year OS was 0.90 (SE = 0.09). CONCLUSION: Rapid central pathology review and molecular testing was feasible. The protocol therapy was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts.
A systematic review of racial disparities in enrollment into clinical trials and clinical outcomes in men with metastatic prostate cancer.
Authors: Oluwadolapo D Lawal, Irene M Shui, Sameer Ghate
Journal: Journal of Clinical Oncology (2022)

e17028 Background: Men of African ancestry have a disproportionately higher incidence of prostate cancer than Caucasians. Yet, men of African ancestry have historically been underrepresented in clinical trials for metastatic prostate cancer (MPC). Further, differences in the magnitude of clinical benefit from treatment by race have been reported. The objective of this study was to assess the racial disparities in clinical trial enrollment of men with MPC and the magnitude of difference in clinical benefit between men of African ancestry and Caucasians with MPC. Methods: A systematic review of MEDLINE was conducted to identify studies published between January 2001 to May 2021. We included: (a) studies that enrolled adults with metastatic castration-resistant prostate cancer (mCRPC) or metastatic hormone sensitive prostate cancer; (b) clinical trials with complete race-stratified frequencies for enrolled subjects; or (c) clinical trials or observational studies that reported race-stratified subgroup analyses or adjusted effect estimates for efficacy/effectiveness outcomes. Outcome measures included overall survival (OS) and progression-free survival (PFS). Results: Of 2,140 retrieved articles, 39 studies involving 39,181 subjects met eligibility criteria. The majority of the studies (n = 35) enrolled mCRPC subjects. Of the 39 studies, 24 were clinical trials and 15 were observational studies. Twenty-one studies enrolled only patients in the US while 18 were multinational studies. Of the 15,761 subjects enrolled in clinical trials, 1750 (11.1%) were men of African ancestry and 12,321 (78.1%) Caucasian. The median (interquartile range) enrollment rate of men of African ancestry in clinical trials was 5.7% (2.3%, 10.1%). Of the 39 eligible studies, 15 reported race-stratified clinical outcomes. Three studies compared men of African ancestry vs Caucasians, 2 men of African ancestry vs non-African ancestry, 3 Caucasian vs others or vice-versa. The remaining 7 studies reported separate estimates on survival by race. All 5 studies comparing men of African ancestry versus other racial groups were conducted in mCRPC subjects. No difference in survival risks by race was observed in the 3 studies that compared men of African ancestry vs Caucasian (HR: 1.09 [0.77, 1.53], 0.68 [0.36, 1.29] and 1.05 [0.97, 1.14]). HRs of 0.90 [0.52, 1.57] and 0.76 [0.61, 0.95] were reported in the 2 studies comparing OS in men of African ancestry vs non-African ancestry. No studies reported a significant increased risk of death by race. Conclusions: Overall, men of African ancestry were largely underrepresented in MPC clinical trials. Concerted efforts are needed to increase the enrollment of this at-risk population in future clinical trial programs. Additional studies are needed to confirm the absence of differences in survival by race in real-life settings.
Outcomes from practice of Retrograde Intrarenal Surgery (RIRS) in a paediatric setting of various age groups: A global study across 8 centres
Authors: E.J. Lim, O. Traxer, Y.Q. Madarriaga, D. Castellani, K. Fong, V.W-S. Chan, A.B. Tur, A. Pietropaolo, D. Ragoori, A. Shrestha, C.M. Vaddi, T.P. Bhatia, M. Mani, P. Juliebø-Jones, S. Griffin, E.G. Rojo, M. Corrales, C.A. Sekerci, Y. Tanidir, J.Y-C. Teoh, V. Gauhar, B.K. Somani
Journal: European Urology (2022)
GRN300–001: Phase 1/1B evaluation of the safety, pharmacokinetics, and efficacy of GRN-300, a salt-inducible kinase inhibitor, alone and in combination with paclitaxel, in recurrent ovarian, primary peritoneal, and fallopian tube cancers.
Authors: Siqing Fu, Amir A. Jazaeri, Zhen Lu, Markus Peter, Stephan Wade Morris, Robert C. Bast
Journal: Journal of Clinical Oncology (2022)

TPS5616 Background: Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of Class IIa HDACs. SIK2 is overexpressed in 30% of ovarian cancers and associated with decreased progression-free survival (Ahmed et al., 2010). Treatment with GRN-300, an orally bioavailable small-molecule inhibitor of SIK2, was shown to improve the response to paclitaxel in human ovarian cancer cells grown in culture and in immunocompromised mice (Zhou et al., 2017). Methods: Part 1 of the study will evaluate the safety, MTD, RP2D (Recommended Phase 2 Dose), and PK of daily GRN-300 monotherapy. For the dose-escalation enrollment of patients with advanced solid tumors of any histology, four dose levels of GRN-300 are planned: 100, 200, 300, and 400 mg BID. Subsequently, GRN-300 will be administered at the determined RP2D in an ovarian cancer expansion cohort. Part 2 will evaluate the safety, PK, and preliminary clinical activity in an open-label study of the combination of GRN-300 and paclitaxel weekly x3. Paclitaxel will be administered in one of two different dosing levels: 60 mg/m2 initially, then dose escalated to 80 mg/m2. In the combination regimen, GRN-300 will be administered at the RP2D dose as determined in Part 1 of this study. The two dose findings will be conducted independently using the BOIN design (Liu 2015, Yuan 2016). Study drug may be administered per protocol for continuous 28-day cycles until disease progression, adverse events, or other criteria as described in the protocol. Tumor biopsies and blood plasma samples including peripheral blood mononuclear cells (PBMCs) will be collected for exploratory biomarker analysis to predict and to monitor responses to GRN-300 treatment. Major eligibility criteria At least 18 years of age. Recurrent or persistent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer (advanced solid tumors of any other histology only for the monotherapy dose escalation enrollment in Part 1) In Part 2, diagnosis of recurrent or persistent, locally non-resectable or metastatic ovarian, primary peritoneal or fallopian tube epithelial cancer for which treatment with paclitaxel is indicated. Received at least one prior second-line treatment. The first 3 dose groups (100, 200, and 300 mg BID of GRN-300) have been completed without DLT and preliminary PK analysis indicate dose proportionality. Enrollment to dose group 4 (400 mg BID) began in February 2022. Clinical trial information: NCT04711161.